624
D. Harel et al. / Journal of Ethnopharmacology 137 (2011) 620–625
with 0.1% formic acid in water (A): methanol (B) gradient elution
from 30 to 100% B in 10 min followed by isocratic elution with 100%
B over 6 min.
3.5. 1-(7-Methoxy-2,2-dimethyl-2H-chromen-6-yl)ethanone (7)
Under N2 compound 6 (1.20 g, 5.49 mmol) was dissolved in ace-
tone (15 mL). Anhydrous K2CO3 (0.84 g, 6.05 mmol) was added, the
mixture was cooled to 0 ◦C and methyl iodide (0.78 g, 5.49 mmol)
was added dropwise. The reaction mixture was stirred under
nitrogen atmosphere for 8 h at room temperature. Then the mix-
ture was filtered through a sintered glass funnel, the filtrate was
concentrated in vacuum and the residue was purified by flash chro-
matography (petroleum ether/ethyl acetate = 80/20, 3 cm, 15 cm,
20 mL, Rf = 0.27) to yield pale yellow oil, yield 1.01 g, (80%). HPLC
purity: 97.8%, tR = 19.9 min. FT-IR (neat): ꢁ (cm−1) = 2974 (C–H),
1662 (C O), 1605 (C–O). Exact mass (ESI): m/z = calculated for
C14H17O3 233.1178, found 233.1104. MS (EI): m/z [%] = 232 (M, 21),
217 (M–CH3, 100). 1H NMR (CDCl3): ı (ppm) = 1.43 (s, 6H, CH3), 2.55
(s, 3H, CH3C O), 3.86 (s, 3H, O–CH3), 5.51 (d, J = 9.8 Hz, 1H, 3-CH),
6.29 (d, J = 9.8 Hz, 1H, 4-CH), 6.37 (s, 1H, 8-CH), 7.52 (s, 1H, 5-CH).
13C NMR (CDCl3): ı (ppm) = 28.6 (2C, CH3), 32.1 (1C, CH3C O), 55.8
(1C, O–CH3), 77.8 (1C, C-2), 99.8 (1C, C-8), 114.2 (1C, C-4a), 120.8,
121.5 (2C, C-4, C-6), 128.6, 129.3 (2C, C-3, C-5), 158.7, 161.3, (2C,
C-7, C-8a), 197.8 (1C, C O).
3.2. 2,2-Dimethylchroman-7-ol (4)
Resorcinol (2) (2.50 g, 22.8 mmol) was dissolved in formic
acid (75 mL) and 2-methylbut-3-en-2-ol (1.96 g, 22.8 mmol) was
added slowly. The mixture was heated to reflux for 8 h. Then
it was cooled down, ice cold H2O (200 mL) was added and the
mixture was extracted with CH2Cl2 (3 × 100 mL). The combined
organic layer was washed with saturated NaHCO3 and then dried
(Na2SO4), concentrated in vacuum and the residue was purified
by flash chromatography ((petroleum ether/ethyl acetate) = 85/15,
5 cm, 15 cm, 30 mL, Rf = 0.29). Colourless solid, m.p. 60–62 ◦C, yield
2.87 g (71%). HPLC purity: 94.7%, tR = 16.6 min. FT-IR (neat): ꢁ
(cm−1) = 3378 (O–H), 2974 (C–H), 1506 (C C aromatic). Exact mass
(ESI): m/z = calculated for C11H15O2 179.1072, found 179.1140. MS
(EI): m/z [%] = 178 (M, 85), 123 (M–CH2 C(CH3)2, 100). 1H NMR
(CDCl3): ı (ppm) = 1.32 (s, 6H, CH3), 1.77 (t, J = 6.8 Hz, 2H, 4-CH2),
2.69 (t, J = 6.8 Hz, 2H, 3-CH2), 6.27 (d, J = 2.6 Hz, 1H, 8-CH), 6.34 (dd,
J = 8.2, 2.6 Hz, 1H, 6-CH), 6.90 (d, J = 8.2 Hz, 1H, 5-CH). 13C NMR
(CDCl3): ı (ppm) = 21.9 (1C, C-4), 27.0 (2C, CH3), 33.1 (1C, C-3), 74.6
(1C, C-2), 104.2, 107.6, 113.5, 130.3, 154.8, 155.1 (6C, Ph-C).
3.6. (RS)-1-(7-Methoxy-2,2-dimethyl-2H-chromen-6-yl)ethanol
(8)
Under N2 compound 7 (0.50 g, 2.15 mmol) was dissolved in
MeOH (10 mL). NaBH4 (0.10 g, 2.58 mmol) was added slowly at
0 ◦C and the reaction mixture was stirred for 2 h at room tem-
perature. Then it was concentrated in vacuum, the residue was
dissolved in water and the solution was extracted with ethyl acetate
(3 × 10 mL). The organic layer was dried (Na2SO4), concentrated
in vacuum and the residue was purified by flash chromatogra-
phy (petroleum ether/ethyl acetate = 80/02, 2 cm, 10 cm, 10 mL,
Rf = 0.27). Colourless liquid, yield 0.49 g, (95%). HPLC purity: 96.8%,
tR = 18.2 min. FT-IR (neat): ꢁ (cm−1) = 3963 (O–H), 2971 (C–H), 1617
(C–O). Exact mass (ESI): m/z = calculated for C14H19O3 235.1334,
found 235.1358. MS (EI): m/z [%] = 234 (M, 27), 219 (M–CH3, 100).
1H NMR (CDCl3): ı (ppm) = 1.41 (s, 3H, CH3), 1.42 (s, 3H, CH3), 1.47
(d, J = 6.5 Hz, 3H, CH3CH), 3.81 (s, 3H, O–CH3), 5.01 (bs, 1H, CHCH3),
5.46 (d, J = 9.8 Hz, 1H, 3-CH), 6.27 (d, J = 9.8 Hz, 1H, 4-CH), 6.37 (s,
1H, 8-CH), 6.94 (s, 1H, 5-CH). 13C NMR (CDCl3): ı (ppm) = 23.1 (1C,
CHCH3), 28.2 (2C, CH3), 55.6 (1C, O–CH3), 65.7 (1C, CHOH), 76.6 (1C,
C-2), 99.7 (1C, C-8), 114.0 (1C, C-4a), 122.2, 124.1 (2C, C-4, C-6),
126.0, 128.1 (2C, C-3, C-5), 153.5, 157.5 (2C, C-7, C-8a).
3.3. 1-(7-Hydroxy-2,2-dimethylchroman-6-yl)ethanone (5)
Chromanol 4 (2.50 g, 11.4 mmol) was dissolved in dry CH2Cl2
(150 mL) and the mixture was cooled to −10 ◦C. Then acetyl
chloride (0.89 g, 11.4 mmol) was added, keeping the reaction tem-
perature below −10 ◦C. Then anhydrous AlCl3 (1.87 g, 11.4 mmol)
was added portion wise over a period of 1 h. After stirring for 30 min
at −5 ◦C, the reaction mixture was poured into ice-cold water and
extracted with CH2Cl2 (3 × 150 mL). The combined organic layer
was washed with saturated NaHCO3, dried (Na2SO4), concentrated
in vacuum and the residue was purified by flash chromatogra-
phy (petroleum ether/ethyl acetate = 90/10, 3 cm, 12 cm, 20 mL,
Rf = 0.27). Colourless solid, m.p. 114–116 ◦C, yield 2.45 g, (75%).
HPLC purity: 97.8%, tR = 19.9 min. FT-IR (neat): ꢁ (cm−1) = 2979
(C–H), 1638 (C O), 1553 (C–O). Exact mass (ESI): m/z = calculated
for C13H17O3 221.1178, found 221.1229. MS (EI): m/z [%] = 220 (M,
60), 165 (M–CH2 C(CH3)2). 1H NMR (CDCl3): ı (ppm) = 1.35 (s, 6H,
CH3), 1.82 (t, J = 6.8 Hz, 2H, 4-CH2), 2.54 (s, 3H, CH3C O), 2.73 (t,
J = 6.8 Hz, 2H, 3-CH2), 6.31 (s, 1H, 8-CH), 7.43 (s, 1H, 5-CH), 12.4
(s, 1H, O-H). 13C NMR (CDCl3): ı (ppm) = 21.9 (1C, C-4), 26.4 (1C,
CH3C O), 27.1 (2C, CH3), 32.9 (1C, C-3), 76.1 (1C, C-2), 104.7, 107.6,
113.5, 114.2, 132.5, 163.2 (6C, Ph), 202.6 (1C, C O).
3.7. [(1RS)-1-(7-Methoxy-2,2-dimethyl-2H-chromen-6-
yl)ethyl]-(Z)-2-methylbutenoate (encecalol angelate, 1)
Under N2 compound 8 (0.15 g, 0.64 mmol) was dissolved in
dry THF (2.5 mL). Angelic acid (80.0 mg, 0.54 mmol) was added
and the reaction mixture was heated in a microwave apparatus
for 10 min. The reaction mixture was concentrated in vacuum
at room temperature. The residue was adsorbed on neutral
aluminum oxide and purified by flash chromatography (Al2O3,
70–230 mesh ASTM, petroleum ether/ether = 80/20, 2 cm, 8 cm,
5 mL, Rf = 0.26). Colourless oil, yield 50.0 mg (35%). FT-IR (ATR,
film): ꢁ (cm−1) = 2972 (C–H), 1714 (C O), 1615, 1576 (C C aro-
matic), 746, 728 (1,2-disubstituted benzene). Exact mass: calcd.
for C19H24NaO4 339.1567, found 339.1558. MS (EI): m/z [%] = 316
(M, 2), 301 (M–CH3, 26), 201 (M–CH3–C5H8O2, 100). 1H NMR
(CDCl3): ı (ppm) = 1.44 (s, 3H, CH3), 1.45 (s, 3H, CH3), 1.53 (d,
J = 6.4 Hz, 3H, CHCH3), 1.92 (quint, 3H, J = 1.5 Hz, CH3C CHCH3),
1.97 (dq, J = 7.1/1.4 Hz, 3H, CH3C CHCH3), 3.79 (s, 3H, OCH3), 5.46
(d, J = 9.8 Hz, 1H, 3-CH), 6.02 (qq, J = 7.2/1.5 Hz, 1H, CH3C CHCH3),
6.24 (q, J = 6.4 Hz, 1H, CH3CH–O), 6.29 (d, J = 9.7 Hz, 1H, 4-CH), 6.35
(s, 1H, 8-CH), 6.96 (s, 1H, 5-CH).
3.4. 1-(7-Hydroxy-2,2-dimethyl-2H-chromen-6-yl)ethanone (6)
Under N2 compound 5 (2.20 g, 9.98 mmol) was dissolved in
toluene (25 mL). DDQ (2.26 g, 9.98 mmol) was added and the reac-
tion mixture was heated to reflux for 3 h. The reaction mixture was
cooled down and filtered through a sintered glass funnel. The fil-
trate was concentrated in vacuum and the residue was purified
by flash chromatography (petroleum ether/ethyl acetate = 90/10,
3 cm, 15 cm, 20 mL, Rf = 0.27). Pale yellow solid, m.p. 72–73 ◦C,
yield 2.13 g, (98%). HPLC purity: 96.6%, tR = 19.8 min. FT-IR (neat):
ꢁ (cm−1) = 2974 (C–H), 1762 (C O), 1639 (C–O). Exact mass (ESI):
m/z = calculated for C13H15O3 219.1021, found 219.1049. MS (EI):
m/z [%] = 218 (M, 47), 203 (M–CH3, 100). 1H NMR (CDCl3): ı
(ppm) = 1.44 (s, 6H, CH3), 2.54 (s, 3H, CH3C O), 5.57 (d, J = 9.8 Hz,
1H, 3-CH), 6.27 (d, J = 9.8 Hz, 1H, 4-CH), 6.33 (s, 1H, 8-CH), 7.31 (s,
1H, 5-CH), 12.7 (s, 1H, O–H).